Imino-sugar c-glycosides, preparation and use thereof

Abstract

The present disclosure relates to iminosugar derivatives and processes for the preparation thereof. The disclosed compounds have glycosidase inhibiting properties, and are useful in the treatment of various diseases, such as type 2 diabetes, neurodegenerative diseases or lysosomal storage disorders. The present disclosure also relates to pharmaceutical compositions containing the disclosed compounds and to their use as biochemical tools.

1 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R1 represents an alkyl (C1-C10) group, an alkenyl (C2-C10) group, an alkynyl (C2-C10) group, a cycloalkyl (C3-C10) group, a heterocycle (C3-C18) group, an aryl (C6-C18) group, or an arylalkyl group; 
         R2 represents a hydrogen atom, an alkyl (C1-C10) group, an alkenyl (C2-C10) group, an alkynyl (C2-C10) group, a cycloalkyl (C3-C10) group, a heterocycle (C3-C18) group, an aryl (C6-C18) group, an arylalkyl group, or a heteroaryl (C4-C16) group; and 
         R3 represents a hydrogen atom, an alkyl (C1-C10) group, an alkenyl (C2-C10) group, an alkynyl (C2-C10) group, a cycloalkyl (C3-C10) group, a heterocycle (C3-C18) group, an aryl (C6-C18) group, or an arylalkyl group; or 
         any geometrical or optical isomer thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein the compound is of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , wherein the compound is of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound according to  claim 1 , wherein the compound is of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein R2 is a hydrogen atom, an alkyl (C1-C8) group, a cycloalkyl (C3-C10) group, or an alkyl (C8-C10) group substituted with at least one heterocycle, cycloalkyl (C3-C10) group or alkoxy group. 
     
     
         6 . The compound according to  claim 1 , wherein R1 represents an alkyl (C1-C8) group, a cycloalkyl (C3-C10) group, or a heterocycle (C3-C18) group. 
     
     
         7 . The compound according to  claim 1 , wherein the compound is one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein n is an integer from 1 to 10, m is an integer from 1 to 10 and q is an integer from 0 to 9. 
     
     
         8 . A compound of general formula (II): 
       
         
           
           
               
               
           
         
       
       wherein R1 and R2 are as defined in  claim 1  and R represents a halogen atom, or a group containing an aliphatic or aromatic group. 
     
     
         9 . A compound of the formula (IIIa) or (IIIb): 
       
         
           
           
               
               
           
         
       
       wherein R 1  is as defined in  claim 1 . 
     
     
         10 . A process for preparing a compound as defined in  claim 3 , comprising the steps of:
 (i) hydrolyzing a compound of the following formula (III):   
       
         
           
           
               
               
           
         
       
       wherein Bn represents an alcohol protecting group, followed by an esterification reaction, as to replace the nitrile function with an ester group,
 (ii) reducing the ester group as to obtain an alcohol group, and 
 (iii) optionally removing the alcohol protecting groups. 
 
     
     
         11 . A process for preparing a compound as defined in  claim 4 , comprising the steps of:
 (i) reacting a compound of the following formula (IV):   
       
         
           
           
               
               
           
         
       
       wherein Bn represents an alcohol or amine protecting group, so as to obtain a compound of the following formula (V): 
       
         
           
           
               
               
           
         
         (ii) preparing from compound of formula (V) a compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         (iii) preparing from compound of formula (VI) a compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         (iv) preparing from compound of formula (VII) a compound of formula (VIII): 
       
       
         
           
           
               
               
           
         
         (v) preparing from compound of formula (VIII) a compound of formula (IX): 
       
       
         
           
           
               
               
           
         
         (vi) optionally removing the alcohol and amine protecting groups to obtain compound of formula (1): 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . A pharmaceutical composition comprising one or more compounds as defined in  claim 1  and a pharmaceutically acceptable carrier and/or excipient. 
     
     
         13 . A method for inhibiting activity of a glycosidase comprising contacting the glycosidase with a compound of  claim 1 . 
     
     
         14 . (canceled) 
     
     
         15 . A method for treating a disease selected from the group consisting of type 2 diabetes, neurodegenerative diseases, cancers, viral diseases, and a lysosomal storage disorder, wherein said method comprises administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         16 . A method for the treatment of dyslipidaemia, haemostasis or fertility control, wherein said method comprises administering to a subject in need of such treatment an effective amount of a compound of  claim 1 . 
     
     
         17 . The compound of  claim 5 , wherein R2 is a hydrogen atom. 
     
     
         18 . The compound of  claim 6 , wherein R1 is methyl, trifluoromethyl or adamantyl. 
     
     
         19 . The compound of  claim 8 , wherein R is fluoro, alkoxy, halogenoalkoxy, nitrophenoxy, organophosphate, phosphoric acid group, amino acid, peptide, or carbohydrate. 
     
     
         20 . The compound of  claim 19 , wherein alkoxy is methoxy (OMe) or ethoxy (OEt). 
     
     
         21 . The compound of  claim 19 , wherein halogenoalkoxy is —OEtBr. 
     
     
         22 . The process of  claim 10 , wherein the alcohol protecting group is a benzyl group. 
     
     
         23 . The process of  claim 10 , wherein the alcohol protecting groups in step (iii) are removed by hydrogenolysis. 
     
     
         24 . The process of  claim 11 , wherein the alcohol or amine protecting group is a benzyl group. 
     
     
         25 . The method of  claim 13 , wherein the glycosidase is N-acetyl hexosaminidase. 
     
     
         26 . The method of  claim 15 , wherein the neurodegenerative disease is Alzheimer disease. 
     
     
         27 . The method of  claim 15 , wherein the lymosomal storage disorder is selected from the group consisting of Sanfilippo syndrome, Fabry disease, Tay-Sachs disease, and Sandoff disease.